Aberrant methylation and impaired expression of the p15(INK4b) cell cycle regulatory gene in chronic myelomonocytic leukemia (CMML)

Leukemia. 2003 May;17(5):910-8. doi: 10.1038/sj.leu.2402891.

Abstract

The important cell cycle regulatory gene p15(INK4b) has been shown to be inactivated in acute myeloid leukemia and myelodysplastic syndrome. Little is known about the expression and epigenetic modification of this gene in chronic myelomonocytic leukemia (CMML) that belongs to the myelodysplastic/myeloproliferative disorders (MDS/MPD) with a high proportion of blastic transformation. Analysis of bone marrow trephines in a series of 33 CMML cases showed an aberrant p15(INK4b) gene methylation in up to 58% of cases. Methylation was analyzed employing different methylation-specific PCR and genomic sequencing protocols. It turned out to be spread over a broad area of the 5' region and exhibited substantial heterogeneity between cases and even in individual patients. The degree of aberrant methylation was correlated with a reduced mRNA as well as reduced protein expression, and was associated with a higher expression of DNA methyltransferase DNMT 3A. We conclude that aberrant gene methylation is a frequent event in CMML that might contribute to the pathogenesis of this MDS/MPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Transformation, Neoplastic / genetics
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • DNA Methyltransferase 3A
  • DNA Methyltransferase 3B
  • DNA Primers / chemistry
  • DNA, Neoplasm / genetics
  • Enzyme Inhibitors / metabolism
  • Genes, Tumor Suppressor
  • Humans
  • Immunoenzyme Techniques
  • Leukemia, Myelomonocytic, Chronic / genetics*
  • Leukemia, Myelomonocytic, Chronic / pathology
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfites / metabolism
  • Tumor Suppressor Proteins*

Substances

  • CDKN2B protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA Primers
  • DNA, Neoplasm
  • DNMT3A protein, human
  • Enzyme Inhibitors
  • RNA, Messenger
  • Sulfites
  • Tumor Suppressor Proteins
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A